Bone is a dynamic tissue, consisting of cells in a protein matrix, upon which is superimposed a crystalline structure of various calcium salts. Because bone is the primary structural support system for the body of an animal, bone disorders can create substantial problems. Bone disorders include, for example, fractures, suboptimal mechanical competence, suboptimal bone blood perfusion, suboptimal bone healing ability, cancerous transformation (primary and bone metastasis), and infection.
Bone disorders can occur in a variety of manners. For example, bone disorders can result from excessive forces being exerted onto the bone, primary bone conditions, and secondary bone conditions associated with other conditions. Bone conditions include, for example, metabolic bone diseases (MBDs). MBDs are conditions characterized by weakening of bones, which weakening is associated with suboptimal mechanical competence and an increased likelihood of fracturing. Osteoporosis is an example of a MBD. Osteoporosis is characterized by bone degeneration caused by a relative excess of bone resorption. Clinical osteoporosis is found in approximately 25% of postmenopausal women, and subclinical osteoporosis, which is responsible for untold numbers of bone fractures, is far more widespread. Other examples of MBDs include, but are not limited to: Paget's disease, characterized by an abnormal growth of bone such that the bone is larger and weaker than normal bone; and osteogenesis imperfecta, characterized by bones that are abnormally brittle.
In addition to serving as a rigid support for the body of an animal, bone is an organ that responds to various agents. To the extent that bone has the ability to interact with and respond to certain agents, disorders associated with bone conditions can be prevented, diagnosed, or treated using appropriate agents having the ability to interact with and affect a desired response in bone. For example, with regard to osteoporosis, there are certain agents, which are thought to interact with bone and are currently available for the treatment or prevention of the condition. Such agents include: bisphosphonates (e.g., alendronate, risedronate); calcitonin; selective estrogen receptor modulators (SERMs) (e.g., raloxifene); selective androgen receptor modulators (SARMs); growth factors; cytokines; agents used for estrogen or hormone replacement therapy (ET4HRT); and parathyroid hormone (PTH) (e.g., teriparatide).
There are a variety of disadvantages associated with treatment using these known agents. For example, although PTH has some anabolic activity, biphosphonates, calcitonin, SERMs, and ET/RHT are primarily anti-catabolic, operating to limit bone resportion. In this regard, the anti-catabolic compounds only treat osteoporosis in so much as they attempt to keep bone density from further decreasing. There are also various side effects associated with such agents; for example, bisphosphonate treatment is associated with gastrointestinal and esophageal erosion, and has been implicated in osteonecrosis of the jaw; SERM treatment has been associated with deep vein thrombosis and hot flashes; ET4HRT has been implicated in increased risk of breast cancer and cardiovascular disease; and PTH therapy has been suggested to potentially increase risk of osteosarcoma (osteogenic sarcoma), a type of cancer that develops in bone, is characterized by formation of a bone matrix having decreased strength relative to normal non-malignant bone matrix, and which can metastasize to other bones and other organs. See e.g., Bilezikian J P (2006) N Engl J Med 355:2278-2281; Cranney A, Adachi J D (2005) Drug Saf 28:721-730; Marshall J K (2002) Expert Opin Drug Saf 1:71-78; Rossouw J E, et al., Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288:321-333; Vahle J L, et al. (2002) Toxicol Pathol 30:312-321, which are incorporated herein by this reference. There are also various drawbacks associated with the delivery of such known agents to an animal, for example, bisphosphonates demonstrate poor oral bioavailability, calcitonin is not orally deliverable, and PTH must be injected. Additionally, some known agents have a limited capacity to affect bone because they lack a specific affinity for bone. That is to say that, when some of the known agents are delivered to an animal, they are not specifically directed to the bone. In this regard, when some of the known agents are delivered to an animal, they are delivered to non-specific locations in the body of the animal, such that they fail to interact with the bone or require a large dose to affect a response in bone. Also in this regard, when such agents are delivered to an animal, they can be directed to undesirable locations in the body of the animal, resulting in undesirable side effects.
Accordingly, there remains a need in the art for compounds, systems, and methods for treating bone disorders and conditions that satisfactorily address some or all of the above-identified disadvantages.